DESCRIPTION (Applicant's abstract): A frequent and often debilitating consequence of diabetes mellitus is the development of diabetic neuropathy (DN). One of the metabolic abnormalities associated with the onset of DN in both human and animal models is altered signaling through neurotrophic factors and an upregulation of the p75 NTR neurotrophin receptor (p75 NTR) in Schwann cells (SC). Insulin-like growth factor-1 (IGF-1) may act directly on SC through activation of its tyrosine kinase receptor but p75 NTR is the only receptor expressed by SC which can bind nerve growth factor (NGF). Additionally, mature SC express caveolin-1, the primary structural protein present in caveolae. Caveolin-1 can regulate growth factor signaling and genetic evidence supports that changes in caveolin-1 expression is associated with the development of several disease phenotypes. Interestingly, the levels of caveolin-1 are down-regulated in SC following cell stress, a time when p75NTR is upregulated. A significant gap exists in our understanding of the role of caveolin-1 in DN and its relevance to regulating growth factor signaling in SC. Our preliminary data indicates that altered expression of caveolin-1 may regulate cellular responses to glucose and signaling by neurotrophic factors in immortalized Schwann cells. Therefore, the objective of this R21 proposal is to test the innovative idea that changes in caveolin-1 expression may contribute to the altered neurotrophism associated with the development of DN by affecting the cellular response to glucose and signaling through p75 NTR and IGF receptors. Our overall hypothesis is that hyperglycemia decreases the expression of caveolin-1 in SC leading to enhanced p75 NTR-dependent signal transduction and decreased signaling through IGF receptors. Our specific aims are: 1) to determine if changes in caveolin-1 expression directly effects p75 NTR and IGF-1 signal transduction in immortalized SC and 2) to determine the effect of in vivo hyperglycemia on caveolin-1 expression in sciatic nerve. The expected outcome of our studies is that we will identify a putative physiological role for caveolin-1 in mediating neurotrophic signals in DN. Understanding the molecular parameters which regulate neurotrophic signaling in SC may provide insight to help increase the therapeutic efficacy of neurotrophic factors in the treatment of DN.